The role of RIC8A in mouse development and its function in cell-matrix adhesion and actin cytoskeletal organisation
Kuupäev
2016-07-05
Autorid
Ajakirja pealkiri
Ajakirja ISSN
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Kirjastaja
Abstrakt
Hulkrakse organismi normaalse elutegevuse tagamiseks on oluline, et rakud saaksid vahetada otseste või kaudsete suhtlusteede kaudu olulist infot. Transmembraansed G-valk-seoselised retseptorid ja nendega interakteeruvad G valgud (guaniin-nukleotiidi siduvad valgud) on üks levinumaid väliskeskkonnast saadava info kanaleid, mis osalevad mitmete arenguliste, füsioloogiliste ja käitumuslike protsesside reguleerimisel. G-valk-seoselised retseptorid on sihtmärgiks paljudele signaalmolekulidele nagu näiteks hormoonid, neurotransmitterid ja kasvufaktorid aktiveerides seeläbi G valgud, mis omakorda käivitavad rakusisese signaalikaskaadi. Sellisel viisil kutsutakse rakkudes esile vastus, milleks võib olla näiteks migratsioon, jagunemine, või aktsioonipotentsiaali tekkimine. RIC8A on nende signaalikaskaadide asendamatu komponent reguleerides G valkude aktiivsust (nukleotiidivahetusfaktori roll) ning tagades rakus G valkude piisava koguse ja membraanse asetuse (chaperon’i roll). Kuna G-valk-seoselised retseptorid on sihtmärgiks rohkem kui poolele tänapäeva ravimitest, võib ka RIC8A uurimine omada meditsiinilist perspektiivi. RIC8A funktsiooni kohta on imetaja organismis vähe teada ning selle asjaolu parandamiseks analüüsiti antud doktoritöös valgu rolli hiire organismis, täpsemalt embrüogeneesis ja närvisüsteemis. Uurimusest tehti kaks peamist järeldust: RIC8A puudus närvisüsteemis viib tugeva neuro-motoorse häire tekkeni ning RIC8A võib olla vajalik rakkude ja ekstratsellulaarse maatriksi vahelise kontakti saavutamiseks. Viimase hüpoteesi kinnitamiseks uurisime rakk-maatriks interaktsioone kasutades mudelina RIC8A puudulikke primaarseid hiire rakke.
Communication between cells is the key for the proper functioning of multicellular organisms. Sensing the environment for information about changes in the surrounding conditions and signals allows the cell to respond and adjust its properties in concert with the rest of the organism. G-protein coupled receptors (GPCRs), and G proteins (guanine nucleotide-binding proteins) that the former are coupled to, are critical for transducing the extracellular information to the inside of the cell, being involved in a multitude of developmental, physiological and behavioural processes. GPCRs communicate signals acquired through the binding of hormones, neurotransmitters, ions and even light particles to name a few. The subsequent activation of G proteins triggers a complex and a highly regulated intracellular signalling cascade, disturbance of which may result in many types of human diseases, such as cardiovascular, neurological and metabolic, as well as cancer. RIC8, one of the indispensable components of this signalling pathway, interacts directly with G protein α subunits, regulating their activity and abundance in cells. The function of RIC8A in mice is still poorly characterised. The main goal of this thesis was to analyse the phenotypes of three different Ric8a knockout mice: a total knockout (Ric8a-/-) and the specific depletions of Ric8a from the neural precursor cells and from differentiated neurons. Two major conclusions were drawn from this analysis. First, the ablation of RIC8A in the nervous system results in a neuromuscular phenotype and second, the lack of RIC8A results in cell migration defects during gastrulation and neurogenesis, probably due to defective adhesion of cells to the extracellular matrix. To elaborate on the latter finding, the adhesive properties of RIC8A-deficient mouse primary cells were evaluated.
Communication between cells is the key for the proper functioning of multicellular organisms. Sensing the environment for information about changes in the surrounding conditions and signals allows the cell to respond and adjust its properties in concert with the rest of the organism. G-protein coupled receptors (GPCRs), and G proteins (guanine nucleotide-binding proteins) that the former are coupled to, are critical for transducing the extracellular information to the inside of the cell, being involved in a multitude of developmental, physiological and behavioural processes. GPCRs communicate signals acquired through the binding of hormones, neurotransmitters, ions and even light particles to name a few. The subsequent activation of G proteins triggers a complex and a highly regulated intracellular signalling cascade, disturbance of which may result in many types of human diseases, such as cardiovascular, neurological and metabolic, as well as cancer. RIC8, one of the indispensable components of this signalling pathway, interacts directly with G protein α subunits, regulating their activity and abundance in cells. The function of RIC8A in mice is still poorly characterised. The main goal of this thesis was to analyse the phenotypes of three different Ric8a knockout mice: a total knockout (Ric8a-/-) and the specific depletions of Ric8a from the neural precursor cells and from differentiated neurons. Two major conclusions were drawn from this analysis. First, the ablation of RIC8A in the nervous system results in a neuromuscular phenotype and second, the lack of RIC8A results in cell migration defects during gastrulation and neurogenesis, probably due to defective adhesion of cells to the extracellular matrix. To elaborate on the latter finding, the adhesive properties of RIC8A-deficient mouse primary cells were evaluated.
Kirjeldus
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Märksõnad
hiirlased, neurogenees, embrüonaalne areng, G-valgud, geeniekspressioon, molekulaargeneetilised aspektid, loomkatsed, Muridae, neurogenesis, embryogenesis, G-proteins, gene expression, molecular genetic aspects, animal experiments